Insertion of v-Ha-ras (TG.AC mice; zeta-globin promoted v-Ha-ras) into FVB mice eliminates the initiation step in carcinogen initiated and promoted mouse skin tumorigenesis. Along with point mutations in both v-Ha-ras and c-Ha-ras, trisomies of chromosomes 6 and 7, c-Ha-ras allelic imbalance, and LOH on chromosome 7 have been reported to be associated with tumor progression from benign papillomas to squamous cell carcinomas or spindle cell tumors. Sequential topical application of tumor promoting agents to TG.AC (zeta-globin promoted v-Ha-ras initiated) transgenic mice resulted in papilloma induction followed by the appearance of disc-shaped soft tissue masses with an ulcerating surface. Karyotypic analysis of these tumors indicated a highly consistent pattern of trisomy of chromosomes 10 and 6 and monosomy of chromosome 13. The spindle shaped cells from primary cultures were highly tumorigenic when transplanted to 9 to 11 day old syngeneic recipients, resulting in large disc-shaped or larger oval shaped ulcerating tumors within approximately two weeks. Western analysis of these transplanted tumors indicate that the transgene (v-Ha-ras) is highly expressed compared to normal skin from transgenic animals and induced papillomas. These results indicate that these spindle shaped cell tumors initiated by insertion of this v-Ha-ras transgene followed by chemical promotion involve complex chromosome arrangements which may be important in identifying other oncogenes and/or tumor suppressor genes involved in skin tumorigenesis.